The invention resides in the technical fields of immunology and medicine.
Alzheimer""s disease (AD) is a progressive disease resulting in senile dementia. See generally Selkoe, TINS 16, 403-409 (1993); Hardy et al., WO 92/13069; Selkoe, J. Neuropathol. Exp. Neurol. 53, 438-447 (1994); Duff et al., Nature 373, 476-477 (1995); Games et al., Nature 373, 523 (1995). Broadly speaking the disease falls into two categories: late onset, which occurs in old age (65+ years) and early onset, which develops well before the senile period, i.e, between 35 and 60 years. In both types of disease, the pathology is the same but the abnormalities tend to be more severe and widespread in cases beginning at an earlier age. The disease is characterized by at least two types of lesions in the brain, senile plaques and neurofibrillary tangles. Senile plaques are areas of disorganized neuropil up to 150 xcexcm across with extracellular amyloid deposits at the center visible by microscopic analysis of sections of brain tissue. Neurofibrillary tangles are intracellular deposits of microtubule associated tau protein consisting of two filaments twisted about each other in pairs.
The principal constituent of the plaques is a peptide termed Axcex2 or xcex2-amyloid peptide. Axcex2 peptide is an internal fragment of 39-43 amino acids of a precursor protein termed amyloid precursor protein (APP). Several mutations within the APP protein have been correlated with the presence of Alzheimer""s disease. See, e.g., Goate et al., Nature 349, 704) (1991) (valine717 to isoleucine); Chartier Harlan et al. Nature 353, 844 (1991)) (valine717 to glycine); Murrell et al., Science 254, 97 (1991) (valine717 to phenylalanine); Mullan et al., Nature Genet. 1, 345 (1992) (a double mutation changing lysine595-methionine596 to asparagine595-leucine596). Such mutations are thought to cause Alzheimer""s disease by increased or altered processing of APP to Axcex2, particularly processing of APP to increased amounts of the long form of Axcex2 (i.e., Axcex21-42 and Axcex21-43). Mutations in other genes, such as the presenilin genes, PS1 and PS2, are thought indirectly to affect processing of APP to generate increased amounts of long form Axcex2 (see Hardy, TINS 20, 154 (1997)). These observation s indicate that Axcex2, and particularly its long form, is a causative element in Alzheimer""s disease.
McMichael, EP 526,511, proposes administration of homeopathic dosages (less than or equal to 10xe2x88x922 mg/day) of Axcex2 to patients with preestablished AD. In a typical human with about 5 liters of plasma, even the upper limit of this dosage would be expected to generate a concentration of no more than 2 pg/ml. The normal concentration of Axcex2 in human plasma is typically in the range of 50-200 pg/ml (Seubert et al., Nature 359, 325-327 (1992)). Because EP 526,511""s proposed dosage would barely alter the level of endogenous circulating Axcex2 and because EP 526,511 does not recommend use of an adjuvant, as an immunostimulant, it seems implausible that any therapeutic benefit would result.
By contrast, the present invention is directed inter alia to treatment of Alzheimer""s and other amyloidogenic diseases by administration of Axcex2, other active immunogen or antibody to Axcex2 to a patient under conditions that generate a beneficial immune response in the patient. The invention thus fulfills a longstanding need for therapeutic regimes for preventing or ameliorating the neuropathology and, in some patients, the cognitive impairment associated with Alzheimer""s disease.
In one aspect, the invention provides methods of preventing or treating a disease characterized by amyloid deposit in a patient. Such methods entail administering an effective dosage of an antibody that specifically binds to the amyloid deposit or a component thereof to the patient. Such methods are particularly useful for preventing or treating Alzheimer""s disease in which case the amyloid deposit is Axcex2. The methods can be used on both asymptomatic patients and those currently showing symptoms of disease.
The antibody used in such methods can be a human, humanized, chimeric or nonhuman antibody and can be monoclonal or polyclonal. In some methods, the antibody is prepared from a human immunized with Axcex2 peptide, which human can be the patient to be treated with antibody.
In some methods, the antibody used binds to an epitope within residues 1-28 of Axcex2. In some methods the antibody binds to an epitope within residues 1-10, and in some methods within residues 1-5. In some methods, the antibody specifically binds to Axcex2 peptide without binding to full-length amyloid precursor protein (APP).
In some methods antibody is administered at a dosage of at least 1 mg/kg body weight antibody. In some methods, the antibody is administered in multiple dosages over a period of at least six months. In some methods, the antibody is administered as a sustained release composition. The antibody can be administered, for example, intraperitoneally, orally, subcutaneously, intracranially, intramuscularly, topically or intravenously.
In some methods, the antibody is administered by administering a polynucleotide encoding at least one antibody chain to the patient. The polynucleotide is expressed to produce the antibody chain in the patient. Optionally, the polynucleotide encodes heavy and light chains of the antibody. The polynucleotide is expressed to produce the heavy and light chains in the patient.
In some methods, the patient is monitored for level of administered antibody in the blood of the patient.
In another aspect, the invention provides methods of preventing or treating Alzheimer""s disease. These methods entail administering an effective dosage of a polypeptide comprising an active fragment of AD that induces an immune response to Axcex2 in the patient. In some methods, the fragment comprises an epitope within amino acids 1-12 of Axcex2. In some method, the fragment comprises an epitope within amino acids 1-16 of Axcex2. In some methods, the fragment comprises an epitope within amino acids 13-28 of Axcex2. In some methods, the fragment is free of at least the 5 C-terminal amino acids in Axcex243. In some methods, the fragment comprises up to 20 contiguous amino acids from Axcex2. Fragments are typically administered at greater than 10 micrograms per dose per patient.
In some methods, the fragment is administered with an adjuvant that enhances the immune response to the Axcex2 peptide. The adjuvant and fragment can be administered in either order of together as a composition. The adjuvant can be, for example, alum, MPL, QS-21 or incomplete Freund""s adjuvant.
The invention further provides pharmaceutical compositions comprising active fragments of Axcex2, such as described above, and an adjuvant.
The invention further provides methods of screening an antibody to Axcex2 or an active fragment of Axcex2 for use in treatment of Alzheimer""s disease. Such methods entail administering an antibody that specifically binds to Axcex2 or a fragment of Axcex2 to a transgenic animal disposed to develop characteristics of Alzheimer""s disease. One then detects a reduction in the extent or rate of development of the characteristics relative to a control transgenic animal as a measure of the efficacy of the antibody or fragment. Optionally, antibodies can also be screened for capacity to bind an epitope within amino acids 1-28 or other epitope of Axcex2.